Histamine is a pleiotropic mediator, involved in a variety of physiological processes including neurotransmission, endocrine and vascular functions. It is also intricately involved in inflammation, upon binding to one or more of the four histamine receptors (H1-4R). H4Rs are predominantly expressed by haemopoietic cells such as T cells, as well as mast cells, basophils, monocytes and neutrophils.
Considerable advances in understanding the role of H4R have been made since the development of H4R agonists and antagonists and studies with H4R knockout mice (Tiligada, Zampeli et al. 2009; Zampeli and Tiligada 2009). Evidence suggests that the H4R can be proinflammatory for several in vivo models of inflammation. In contrast, using a mouse model of airway hyper responsiveness, administration of the H4R agonist 4-methyl histamine was anti-inflammatory and reduced airway hyper responsiveness (Morgan, McAllister et al. 2007). In that in vivo model an increase in regulatory T cells (Treg) was also observed, suggesting a mechanism whereby H4R stimulation mediates anti-inflammatory responses. Single-nucleotide polymorphisms (SNPs, pronounced snip) analysis of patients with Systemic Lupus Erythematosus (SLE) and psoriasis has identified an association with human H4R (Yu, Shao et al. 2010), suggesting a link between H4R and clinical disease. In a recent study of H4R knockout mice induced for experimental autoimmune encephalomyelitis (EAE), a CD4+T cell-mediated mouse model of multiple sclerosis, it has been found that the H4R gene deficient mice demonstrated an increase in EAE disease severity and enhanced blood-brain barrier permeability, despite having similar numbers of effector CD4+ T cells (del Rio, Noubade et al. 2012). Interestingly, there were fewer Treg in the CNS of these mice, resulting in increased levels of effector Th17 cells. These data would agree with the hypothesis that H4R is playing an important role in regulating inflammation.
The inventors tested the efficacy of H4R antagonists in two models of uveitis: experimental autoimmiune uveitis (EAU) and endotoxin induced uveitis (EIU) and were surprised to find that they were effective against both conditions. EIU is an innate cell mediated condition, specifically it is mediated by neutrophils. It is brought about by injecting a model animal with bacterial endotoxin, a lipopolysaccharide (LPS). Experimental autoimmune uveitis is generally accepted to be T-cell mediated, and so it is surprising that the same antagonists were efficacious against both models.
A large number of H4R modulating compounds are known, and have in some instances been suggested (albeit not actually shown) to be of potential usefulness in autoimmune uveitis. Such modulators can be found, for example, in Sander et at (Bioorg. Med. Chem. (2009) 17, 7186), Schreeb et al. (Pharmazie (2013) 68, 521), Sava11 (Annual Meeting of the European Histamine Research Society, May 2013, Programme and Abstracts, p 48), Zampeli et at (Inflamm Res. (2009) 58, 285), US 2009/0075970, US 2005/0070550, US 2010/0240671, US 2007/0238771, EP 2270002 A1, WO 2007/031529, WO2009/056551, WO 2009/068512, WO 2009/077608, WO 2009/080721, WO 2009/115496. Lazewska et at (Frontiers in Bioscience (2012), S4, 967), WO2012/041860, WO2011/076878A1, WO2010/075270A1, WO2009/047255, WO2009/134726, WO2001/085786, WO2009/038673, WO2008/060766, WO2005/031308, WO2008/003702, WO2007/117401, WO2010/072829, WO2008/006974, WO2004/021999, WO2008/008359, WO2004/022537, WO2003/057919, WO2010/108059, WO2002/072548, WO2009/079001, WO2008/100565, WO2007/117400, WO2009/068512, WO2006/050965, WO2001/092485, WO2010/146173, WO2009/071625, WO2004/022060, and WO2004/066960. The contents of each of these documents, and in particular the H4R modulators disclosed therein, are incorporated herein in their entirety by reference.